Thienopyrimidinediones and their use in modulation of autoimmune disease

ABSTRACT

The invention relates to thienopyrimidinediones of formula (I): 
     
       
         
         
             
             
         
       
     
     in which R 1 , R 2 , Q are as defined in the specification, and Ar and Ar 2  are selected from certain aromatic ring systems which may be optionally substituted, as defined in the specification. 
     Processes for the preparation of compounds of formula (I), pharmaceutical compositions containing them and their use in therapy are also described.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/542,457, filed on Jul. 14, 2005, which is the national phaseapplication of International Application No. PCT/SE2004/000053, filedJan. 15, 2004, which claims the benefit of Swedish Patent ApplicationSerial No. 0300117-9, filed Jan. 17, 2003 and Swedish Patent ApplicationSerial No. 0300118-7, filed Jan. 17, 2003. The contents of all parentapplications are hereby incorporated by reference in their entireties.

BACKGROUND

The present invention relates to thienopyrimidinediones, processes fortheir preparation, pharmaceutical compositions containing them and theiruse in therapy. The invention also relates to their use in themodulation of autoimmune disease.

T-cells play an important role in the immune response, however inauto-immune disease T-cells are inappropriately activated againstparticular tissues and proliferate, e.g., causing the inflammationassociated with rheumatoid arthritis. Inhibition of the proliferation ofT-cells is beneficial in the modulation of autoimmune disease. Thepresent invention relates to compounds which are beneficial in themodulation of autoimmune disease.

DETAILED DESCRIPTION

In accordance with the present invention, there is provided a compoundof formula (I):

in which R¹ and R² each independently represent C₁₋₆alkyl, C₃₋₆alkenyl,C₃₋₅cycloalkylC₁₋₃alkyl or C₃₋₆cycloalkyl, each of which is optionallysubstituted by 1 to 3 halogen atoms; Q is CR⁴R⁵ where R⁴ is hydrogen,fluorine or C₁₋₆ alkyl and R⁵ is hydrogen, fluorine or hydroxy; Ar is a5- to 10-membered aromatic ring system in which up to 4 ring atoms areheteroatoms independently selected from the group consisting ofnitrogen, oxygen and sulphur, the ring system being optionallysubstituted by one or more substituents independently selected from thegroup consisting of C₁₋₄alkyl (optionally substituted by 1, 2 or 3hydroxy or halo groups), C₁₋₄alkoxy, halogen, C₁₋₄alkoxyC₁₋₄alkyl,C₁₋₄alkylthio, C₁₋₄alkoxycarbonyl, C₂₋₄alkanoyl, oxo, thioxo, nitro,cyano, —N(R⁶)R⁷, —(CH₂)pN(R⁸)R⁹, hydroxy, C₁₋₄alkylsulphonyl,C₁₋₄alkylsulphinyl, carbamoyl, C₁₋₄alkylcarbamoyl,di-(C₁₋₄alkyl)carbamoyl, carboxy, SO₂N(R⁸)R⁹; Ar² is a 5 or 6 memberedaromatic ring containing up to 4 hetero atoms independently selectedfrom the group consisting of nitrogen, sulphur or oxygen, and which isoptionally substituted by one or more groups independently selected fromthe group consisting of C₁₋₄alkyl (optionally substituted by 1,2 or 3hydroxy or halo groups), C₁₋₄alkoxy, halogen, C₁₋₄alkoxyC₁₋₄alkyl,C₁₋₄alkylthio, C₁₋₄alkoxycarbonyl, C₂₋₄alkanoyl, oxo, thioxo, nitro,cyano, —N(R⁶)R⁷, —(CH₂)pN(R⁸)R⁹, hydroxy, C₁₋₄alkylsulphonyl,C₁₋₄alkylsulphinyl, carbamoyl, C₁₋₄alkylcarbamoyl,di-(C₁₋₄alkyl)carbamoyl, carboxy, SO₂N(R⁸)R⁹; p is 1 to 4; R⁶ and R⁷each independently represent a hydrogen atom, C₁₋₄alkanoyl or C₁₋₄alkylgroup, or together with the nitrogen atom to which they are attachedform a 5- to 7-membered saturated heterocyclic ring optionallycontaining a further O, S, NH or N-alkyl group; R⁸ and R⁹ eachindependently represent a hydrogen atom, C₁₋₄alkanoyl or C₁₋₄alkylgroup, or together with the nitrogen atom to which they are attachedform a 5- to 7-membered saturated heterocyclic ring optionallycontaining a further O, S, NH or N-alkyl group; and pharmaceuticallyacceptable salts and solvates thereof, provided that the compound isother than5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methyl-6-[5-methyl-3-phenyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,6-[[3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dioneor6-[[3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dioneor a pharmaceutically acceptable salt or solvate thereof.

Suitably R¹ is C₁₋₆ alkyl or C₃₋₆ cycloalkyl, and in particular C₁₋₆alkyl. More preferably R¹ is ethyl, propyl, butyl or cyclopropyl. Mostpreferably R¹ is ethyl, isobutyl, isopropyl or cyclopropyl.

More preferably R¹ is C₁₋₄ alkyl such as isobutyl or isopropyl.

Preferably R² is C₁₋₆alkyl such as ethyl or methyl, more preferablymethyl.

Suitably Q is CR⁵R⁶ where R⁵ is hydrogen, C₁₋₆ alkyl and R⁶ is hydrogen.Preferably Q is CR⁴R⁵ where R⁴ and R⁵ are both hydrogen.

Examples of 5-10 membered mono- or bi-cyclic aromatic ring systems forAr include thienyl, furanyl, pyrrolyl, pyrrolopyridino, imidazolyl,pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl, oxazolyl,thiazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,tetrazolyl and quinolyl.

Examples of 5- to 7-membered saturated heterocyclic rings formed by R⁶and R⁷ and R⁸ and R⁹ include morpholine, piperidine, N-alkyl piperidine,piperazine, pyrrolidine and the like. Preferably Ar is a 5 or 6-memberedaromatic ring system wherein up to 2 ring atoms may be heteroatomsindependently selected from nitrogen, oxygen and sulphur, the ringsystem being optionally substituted by one or more substituentsindependently selected from C₁₋₄alkyl, C₁₋₄alkoxy, halogen,haloC₁₋₄alkyl, dihaloC₁₋₄alkyl, trihaloC₁₋₄alkyl, oxo, thioxo, cyano, orC₁₋₄alkylsulphonyl.

More preferably Ar is 5-membered aromatic ring containing two nitrogenatoms and substituted as above.

A particular example of Ar is an optionally substituted pyrazole ring.Preferably Ar is a substituted pyrazole ring.

Most preferably Ar is a pyrazole ring di-substituted by C₁₋₄alkyl,especially methyl.

For instance, Ar is suitably a group of sub-formula (I):

where R¹⁰ and R¹¹ are independently selected from H, C₁₋₄alkyl,haloC₁₋₄alkyl, dihaloC₁₋₄alkyl, or trihaloC₁₋₄alkyl, and Ar² is asdefined above.

In R¹⁰ and R¹¹ are selected from H or C₁₋₃alkyl, such as methyl. Inparticular, both R¹⁰ and R¹¹ is C₁₋₃alkyl such as methyl.

Ar² is suitably a 5 or 6-membered aromatic ring system wherein up to 3ring atoms may be heteroatoms independently selected from nitrogen,oxygen and sulphur, the ring system being optionally substituted by oneor more substituents independently selected from C₁₋₄alkyl, C₁₋₄alkoxy,halogen, dihaloalkyl, trihaloalkyl, oxo, thioxo, cyano,C₁₋₄alkylsulphonyl.

Preferably Ar² is other than phenyl. In particular Ar² includes at leastone heteroatom.

Examples of haloalkyl groups are haloC₁₋₄alkyl groups which includehalomethyl groups such as fluoroethyl groups. Examples of dihaloalkylgroups are dihaloC₁₋₄alkyl groups including difluoromethyl anddichloromethyl. Examples of trihaloalkyl groups are trihaloC₁₋₄alkylgroups such as trifluoromethyl.

In a preferred embodiment, Ar² is 5-membered aromatic ring containing anitrogen and sulphur atom and substituted as above. Most preferably Ar²is a thiazole ring substituted by halogen, especially fluoro.

In an alternative embodiment of the invention, Ar² is pyridine orpyrimidine. The rings carry at least one substituent, but are preferablyunsubstituted.

Preferably Ar² is pyridinyl or pyrimidinyl.

Preferred compounds of formula (I) include6-[[3,5-dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]methyl]-5-[[(4S)-4-hydroxy-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,and6-[[3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazol-4-yl]methyl]-5-[[(4S)-4-hydroxy-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,and pharmaceutically acceptable salts thereof.

Other preferred compounds of formula (I) include(S)-2-[[6-[[3,5-dimethyl-1-(2-thiazolyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-isoxazolidinoland pharmaceutically acceptable salts thereof.

Alkyl groups, whether alone or as part of another group, can be straightchained or branched. Unless otherwise stated, they may contain from 1 to6, and preferably from 1 to 4 carbon atoms.

It will be understood that a compound of the formula (I) or a saltthereof may exhibit the phenomenon of tautomerism and that the drawingswithin this specification represent only one of the possible tautomericforms. It is to be understood that the invention encompasses anytautomeric form.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of the compounds offormula (I) and mixtures thereof including racemates. These also form anaspect of the present invention.

Salts for use in pharmaceutical compositions will be pharmaceuticallyacceptable salts, but other salts may be useful in the production of thecompounds of formula (I) and their pharmaceutically acceptable salts.Pharmaceutically acceptable salts of the invention may, for example,include acid addition salts of the compounds of formula (I) ashereinbefore defined which are sufficiently basic to form such salts.Such acid addition salts include for example salts with inorganic ororganic acids affording pharmaceutically acceptable anions such as withhydrogen halides (especially hydrochloric or hydrobromic acid of whichhydrochloric acid is particularly preferred) or with sulphuric orphosphoric acid, or with trifluoroacetic, citric or maleic acid.Suitable salts include hydrochlorides, hydrobromides, phosphates,sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates,acetates, benzoates, citrates, maleates, fumarates, succinates, lactatesand tartrates. In addition where the compounds of formula (I) aresufficiently acidic, pharmaceutically acceptable salts may be formedwith an inorganic or organic base which affords a pharmaceuticallyacceptable cation. Such salts with inorganic or organic bases includefor example an alkali metal salt, such as a sodium or potassium salt, analkaline earth metal salt such as a calcium or magnesium salt, anammonium salt or for example a salt with methylamine, dimethylamine,trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

Preferred salts include an acid addition salt such as a hydrochloride,hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate,oxalate, methanesulfonate or p-toluenesulfonate, or an alkali metal saltsuch as a sodium or potassium salt.

In a further aspect the invention provides a process for the preparationof a compound of formula (I) which comprises:

(a) reaction of a compound of formula (II):

in which R¹ and R² are as defined in formula (I) or are protectedderivatives thereof, and X and Y are selected from C₁₋₄alkyl (optionallysubstituted by 1, 2 or 3 hydroxy groups), C₁₋₄alkoxy, haloalkyl,dihaloalkyl, trihaloalkyl, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkoxycarbonyl, or—(CH₂)pN(R⁸)R⁹, with a compound of formula (III): Ar²-G1-G2 (III), whereAr² is as defined in formula (I) or are protected derivatives thereofand G1 is NH, G2 is NH₂, SH or OH, or

(b) reacting a compound of formula (IV):

in which R¹, R², Ar and Ar² are as defined in formula (I) or areprotected derivatives thereof, with a compound of formula (V):

in which P is a protecting group, or

(c) for compounds of formula (I) where Ar has an NH group, reacting acompound of formula (VI):

in which R¹ and R² and as defined in formula (I) and Ar is as defined informula (I) provided Ar has an NH group, or are protected derivativesthereof, with a compound of formula (VII): Ar²-L (VII), in which Ar² isas defined in formula (I) or is a protected derivative thereof and L isa leaving group,

and optionally thereafter process (a), (b) or (c) in any order

removing any protecting groups

forming a pharmaceutically acceptable salt.

Reaction of compounds (II) and (III) is suitably carried out in an inertsolvent (e.g., ethanol) at a temperature of from 0° C. to 100° C.,preferably 10° C. to 50° C., optionally in the presence of a catalyticquantity of an acid (e.g., trifluoroacetic acid).

Reaction of compounds (IV) and (V) is carried out by conversion of thecarboxylic acid function to an activated form by reaction with acoupling agent (e.g., EDCI and 1-hydroxybenzotriazole) in an inertsolvent (e.g., dichloromethane) in the presence of a base, preferablytriethylamine or ethyldiisopropylamine, at a temperature of from 0° C.to 100° C., preferably 10° C. to 50° C., in the presence of compound(V).

Reaction of compounds (VI) and (VII) is carried out either by heating inan inert solvent such as NMP in the presence of a base, for example ametal carbonate, under microwave irradiation; or by use of catalytic (orstoicheiometric) Buchwald conditions using a Cu(I) salt with a diamineligand in a solvent such as dioxan at a temperature of about 100° C. Thegroup L is any suitable leaving group, preferably L is halogen.

Compounds of formula (II) can be prepared by reacting a compound offormula (VIII):

in which R¹, R² and P are as defined above and L is a leaving group witha nucleophilic fragment of a the group Ar such as a zinc salt of abeta-diketone. L is preferably a halogen such as bromo.

Compounds of formula (VIII) can be prepared from compounds of formula(IX):

in which R¹, R² and P are as defined above by, for example, brominationusing N-bromosuccinimide in an inert solvent such as chloroform under alight source at a temperature of from 15° C. to 80° C., preferably at50° C. to 70° C.

Compounds of formula (IX) can be prepared by protection of thecorresponding alcohols of formula (X):

in which R¹, R² and P are as defined above by, for example, reactingwith a trialkylsilyl halide in an inert solvent such as dichloromethaneat a temperature of from 0° C. to 60° C., preferably 10° C. to 30° C.,in the presence of a base such as imidazole.

Compounds of formula (X) can be prepared from acids of formula (XI):

in which R¹, R² and P are as defined above by forming an acid chlorideby treating with a reagent such as oxalyl chloride in an inert solventsuch as dichloromethane at a temperature of from 0° C. to 60° C.,preferably 10° C. to 30° C., followed by treatment of the resulting acidchloride with the hydroxyisooxazolidine in a solvent such asdichloromethane at a temperature of from 0° C. to 60° C., preferably 10°C. to 30° C. in the presence of a base such as triethylamine.

Compounds of formula (XI) are prepared from the corresponding estersusing standard conditions.

Compounds of formula (IV) can be prepared from compounds of formula(XII):

in which R¹, R² and Ar are as defined above, provided that Ar containsan NH group, and R²⁰ is an ester forming group by, for example, reactingwith a compound of formula (XIII): Ar²-halogen (XIII), in which Ar² isas defined above or by reaction with a compound Ar² where Ar is asdefined above provided that Ar contains a nitrogen centre.

Reaction of compounds (XII) and (XIII) can be carried out in an inertsolvent such as dioxan at a temperature of 10° C. to 120° C. in thepresence of a copper (I) salt and an alkylene diamine. The group R²⁰ isan ester forming group such as alkyl, especially methyl.

Reaction of compounds (XII) and Ar² can be carried out in a solvent suchas dimethyl acetamide at a temperature of 10° C. to 200° C. in thepresence of a base such as potassium carbonate optionally with microwaveirradiation.

A compound of formula (XII) can be prepared from a compound of formula(XV):

in which R¹, R² and R²⁰ are as defined above by reaction with a strongbase such as lithium diisopropylamide in a solvent such as THF at −78°C. to 0° C. followed by the addition of a compound of formula (XVI):Ar—CHO (XVI).

Compounds of formula (IV) are prepared from compounds of formula (XVII):

in which R¹, R², R²⁰, Ar and Ar² are as defined above, either bydeoxygenation using a strong acid such as TFA in the presence of ahydride source such as triethylsilane, optionally in a solvent such asdichloromethane at a temperature of 10° C. to 40° C., or by activationof the hydroxyl group by esterification with an activated carboxylicacid such as trifluoroacetic anhydride or methane sulphonyl chloride inan inert solvent such as ethyl acetate followed by hydrogenolysis, forexample using palladium on carbon at 1 to 5 bar at 10° C. to 80° C.

Compounds of formula (XVII) are prepared from compounds of formula (XV)as defined above by reacting with compounds (XVIII): Ar²−Ar—CHO (XVIII),in which Ar and Ar² are as defined above using conditions analogous tothose above for the reaction of compounds (XV) and (XVI).

Compounds of formula (VI) may be made from compounds of formula (XII) byhydrolysis of the ester function (using an alkali metal or alkalineearth hydroxide in a solvent containing water, e.g., aqueous ethanol oraqueous methanol) at a temperature of from 0° C. to 100° C., or usingaqueous mineral acid in an inert solvent at a temperature of from 20° C.to 100° C., and then coupling the acid residue with a compound offormula (V) in the presence of a condensing agent (e.g., PyBrOP) in aninert solvent (e.g., THF) in the presence of a base such astriethylamine at a temperature of from 0° C. to 30° C.

Starting materials as defined above are available commercially or can beprepared using routine chemistry known in the art.

The compounds of the invention are useful because they possesspharmacological activity in human and non-human animals. They areindicated as pharmaceuticals for use in the (prophylactic) treatment ofautoimmune, inflammatory, proliferative and hyperproliferative diseasesand immunologically mediated diseases including rejection oftransplanted organs or tissues and Acquired Immunodeficiency Syndrome(AIDS).

Examples of these conditions are:

(1) (the respiratory tract) airways diseases including chronicobstructive pulmonary disease (COPD); asthma, such as bronchial,allergic, intrinsic, extrinsic and dust asthma, particularly chronic orinveterate asthma (e.g. late asthma and airways hyper-responsiveness);bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitisincluding rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta,rhinitis sicca and rhinitis medicamentosa; membranous rhinitis includingcroupous, fibrinous and pseudomembranous rhinitis and scrofulousrhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) andvasomotor rhinitis; sarcoidosis, farmer's lung and related diseases,fibroid lung and idiopathic interstitial pneumonia;

(2) (bone and joints) rheumatoid arthritis, seronegativespondyloarthropathies (including ankylosing spondylitis, psoriaticarthritis and Reiter's disease), Behcet's disease, Sjogren's syndromeand systemic sclerosis;

(3) (skin) psoriasis, atopical dermatitis, contact dermatitis and othereczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus,bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas,vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopeciaareata and vernal conjunctivitis;

(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilicgastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis,food-related allergies which have effects remote from the gut, e.g.,migraine, rhinitis and eczema;

(5) (other tissues and systemic disease) multiple sclerosis,atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupuserythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis,myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophiliafascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome andidiopathic thrombocytopenia pupura;

(6) (allograft rejection) acute and chronic following, for example,transplantation of kidney, heart, liver, lung, bone marrow, skin andcornea; and chronic graft versus host disease; and

(7) cancer.

Accordingly, the present invention provides a compound of formula (I) ora pharmaceutically acceptable salt thereof as hereinbefore defined foruse in therapy.

In another aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof ashereinbefore defined in the manufacture of a medicament for use intherapy.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

Prophylaxis is expected to be particularly relevant to the treatment ofpersons who have suffered a previous episode of, or are otherwiseconsidered to be at increased risk of, the disease or condition inquestion. Persons at risk of developing a particular disease orcondition generally include those having a family history of the diseaseor condition, or those who have been identified by genetic testing orscreening to be particularly susceptible to developing the disease orcondition.

The invention further provides a method of effecting immunosuppression(e.g., in the treatment of allograft rejection) which comprisesadministering to a patient a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof ashereinbefore defined.

The invention still further provides a method of treating, or reducingthe risk of, an airways disease (e.g., asthma or COPD) in a patientsuffering from, or at risk of, said disease, which comprisesadministering to the patient a therapeutically effective amount of acompound of formula (I) or a pharmaceutically-acceptable salt thereof ashereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated. However, in general,for effecting immunosuppression, the daily dosage of the compound offormula (I) will be in the range from 0.1 mg/kg, preferably from 0.3mg/kg, more preferably from 0.5 mg/kg and still more preferably from 1mg/kg up to and including 30 mg/kg. For the treatment of airwaysdiseases, the daily dosage of the compound of formula (I) will typicallybe in the range from 0.001 mg/kg to 30 mg/kg.

The compounds of formula (I) and pharmaceutically-acceptable saltsthereof may be used on their own but will generally be administered inthe form of a pharmaceutical composition in which the formula (I)compound/salt/solvate (active ingredient) is in association with apharmaceutically-acceptable adjuvant, diluent or carrier. Depending onthe mode of administration, the pharmaceutical composition willpreferably comprise from 0.05 to 99% w (percent by weight), morepreferably less than 80% w, e.g. from 0.10 to 70% w, and even morepreferably less than 50% w, of active ingredient, all percentages byweight being based on total composition.

Thus, the present invention also provides a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof as hereinbefore defined, in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I) or a pharmaceutically acceptable salt thereof ashereinbefore defined, with a pharmaceutically acceptable adjuvant,diluent or carrier.

The pharmaceutical composition of the invention may be administeredtopically (e.g. to the lung and/or airways or to the skin) in the formof solutions, suspensions, heptafluoroalkane aerosols and dry powderformulations; or systemically, e.g., by oral administration in the formof tablets, capsules, syrups, powders or granules, or by parenteraladministration in the form of solutions or suspensions, or bysubcutaneous administration or by rectal administration in the form ofsuppositories or transdermally.

The ability of compounds which can inhibit PMA/ionomycin-stimulatedperipheral blood mononuclear cell proliferation can be assessed, forexample using the procedure set out below.

The invention will now be illustrated in the following Examples inwhich, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solidssuch as drying agents by filtration;

(ii) operations were carried out at ambient temperature, that is in therange 18-25° C. and under an atmosphere of an inert gas such as argon ornitrogen;

(iii) yields are given for illustration only and are not necessarily themaximum attainable;

(iv) the structures of the end-products of the formula (I) wereconfirmed by nuclear (generally proton) magnetic resonance (NMR) andmass spectral techniques; proton magnetic resonance chemical shiftvalues were measured on the delta scale and peak multiplicities areshown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br,broad; q, quartet, quin, quintet;

(v) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatography (TLC), high-performance liquidchromatography (HPLC), mass spectrometry (MS), infra-red (IR) or NMRanalysis;

Abbreviations

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DDQ Dimethylformamide DMFTetrahydrofuran THF

The following examples illustrate the invention.

EXAMPLE 16-[[3,5-dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]methyl]-5-[[(4S)-4-hydroxy-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

a) Ethyl methyl2-methyl-5-(N,N-methylethylamino)-thiophene-3,4-dicarboxylate

Ethoxycarbonylmethylene triphenyl phosphorane (33.8 g) in dry THF (200ml) was treated with isopropyl isothiocyanate (10.1 g) at 65° C. for 16hours under nitrogen. The mixture was cooled to −78° C. and methyl3-bromo-2-oxo-butanoate was added. The reaction was allowed to warmslowly to room temperature. After 24 hours at room temperature moremethyl 3-bromo-2-oxo-butanoate (2.8 g) was added and the mixture waswarmed to 60° C. for 16 hours. The cooled reaction was poured into water(1.5 L) and extracted into ether. Drying and evaporation gave an oilwhich was chromatographed (SiO₂/10:1 isohexane-ethyl acetate then 5:1isohexane-ethyl acetate) to afford the sub-title compound (23.5 g).

δ ¹H_(CDC13) 1.23-1.35 (9H, m), 2.26 (3H, s), 3.46 (1H, m), 3.82 (3H,s), 4.2 (2H, q), 7.42 (1H, br.s).

b) Methyl1,2,3,4-tetrahydro-3,6-dimethyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate

Silver cyanate (13.5 g) suspended in anhydrous toluene (90 ml) undernitrogen was treated dropwise with acetyl chloride (5.34 ml) and stirredvigorously for 30 minutes. The product of step a) (23 g) dissolved inanhydrous toluene (15 ml) was added and the mixture was stirred for 72hours. Ether (360 ml) was added and the insoluble material was filteredoff and washed with a small volume of ether. The combined organicsolutions were washed with saturated sodium bicarbonate solution, driedand evaporated. The residue was treated with a solution of sodiummethoxide in methanol (25 wt %, 64 ml) at room temperature for 72 hours.The reaction was cooled in ice and treated with trimethylsilyl chloride(50.8 ml) and stirred at room temperature overnight. All volatiles wereremoved in vacuo and the residue partitioned between water and ethylacetate. Drying and evaporation of the organic solution left a residue,which was chromatographed (SiO₂/2:1 isohexane-ethyl acetate then 3:2isohexane-ethyl acetate) to isolate the major component (12.2 g). Thiswas taken in dry DMF (150 ml) with potassium carbonate (6.95 g) andmethyl iodide (7.1 g) for 72 hours at room temperature. The mixture waspoured into water (2 L), acidified and extracted into ether. Washingwith brine, drying and evaporation gave a solid which was boiled inisohexane (200 ml) containing ethyl acetate (3 ml). On cooling theprecipitated pale yellow solid was collected and dried, to afford thesub-title compound (10.5 g).

MS (APCI) [M+H]⁺ 297.

δ ¹H_(CDC13) 1.6 (6H, d), 2.44 (3H, s), 3.37 (3H, s), 3.95 (3H, s), 4.66(1H, br).

c)1,2,3,4-Tetrahydro-3,6-dimethyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylicacid

To a solution of the product of step b) (3.81 g) in THF (50 ml) andmethanol (5 ml) was added 1N NaOH (25.7 ml) and the mixture stirredunder nitrogen for 18 hours. It was acidified with 2.5 N HCl andextracted with DCM, the organic extracts washed with water, dried overanhydrous magnesium sulfate, filtered and evaporated under reducedpressure to give the sub-title compound as a solid (3.40 g).

MS (ESI) 283 [M+H]⁺.

d)5-[[(4S)-4-Hydroxy-2-isoxazolidinyl]carbonyl]-3,6-dimethyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

To a suspension of the product of part c) (3.40 g) in DCM (50 ml) wasadded oxalyl chloride (1.16 ml) and DMF (10 μl) and the mixture stirredunder nitrogen for 2 hours. The acid chloride solution was added to asuspension of (S)-4-isoxazolidinol hydrochloride (1.51 g) andtriethylamine (3.52 ml) in DCM (20 ml) at 0° C. under nitrogen and themixture stirred at room temperature for 3 hours. It was washed withwater, dried over anhydrous magnesium sulfate, filtered and evaporatedunder reduced pressure. The residue was purified by columnchromatography over silica, eluting with ethyl acetate to give thesub-title compound as a solid (2.52 g).

MS (ESI) 354 [M+H]⁺.

δ ¹H_(DMSO) 1.50-1.52 (6H, m), 2.30-2.34 (3H, m), 3.18-3.19 (3H, m),3.42-4.08 (4H, m), 4.59-4.74 (2H, m), 5.49-5.50 (1H, m).

e)5-[[(4S)-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-2-isoxazolidinyl]carbonyl]-3,6-dimethyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

To a solution of the product of part d) (2.52 g) in DCM (30 ml) wasadded imidazole (0.53 g) and tert-butyldimethylsilyl chloride (1.18 g)and the mixture stirred under nitrogen for 24 hours. It was acidifiedwith 1N HCl and extracted with DCM, the organic extracts washed withwater, dried over anhydrous magnesium sulfate, filtered and evaporatedunder reduced pressure. The residue was purified by columnchromatography over silica, eluting with i-hexane/ethyl acetate (3:1)followed by i-hexane/ethyl acetate (1:1) to give the sub-title compound(2.42 g).

δ¹H_(DMSO) 0.09 (6H, d), 0.86 (9H, s), 1.50 (6H, d), 2.31-2.34 (3H, m),3.18-3.19 (3H, m), 3.44-4.15 (4H, m), 4.50-4.97 (2H, m).

f)6-Bromomethyl-5-[[(4S)-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

to a solution of the product of part e) (2.42 g) in chloroform (100 ml)was added N-bromosuccinimide (1.01 g) and the mixture heated underreflux whilst being irradiated with a 300 W tungsten lamp for 2 hours.It was cooled, washed with 1 N NaOH solution, washed with water, driedover anhydrous magnesium sulfate, filtered and evaporated under reducedpressure to give the sub-title compound (2.83 g).

MS (ESI) 546 and 548 [M+H]⁺.

g)6-(2-Acetyl-3-oxobutyl)-5-[[(4S)-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

A solution of the product of part f) (2.83 g) and zinc acetylacetonatehydrate (1.47 g) in chloroform (50 ml) was heated under reflux for 1hour. It was cooled, washed with sodium bicarbonate solution, filteredthrough celite, washed with brine, dried over anhydrous magnesiumsulfate, filtered and evaporated under reduced pressure to give thesub-title compound (2.93 g).

MS (ESI) 566 [M+H]⁺.

h)5-[[(4S)-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-2-isoxazolidinyl]carbonyl]-6-[[3,5-dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]methyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

To a solution of the product of part g) (0.73 g) in chloroform (25 ml)was added pyrimidin-2-ylhydrazine (0.27 g) and the mixture stirred for48 hours. It was washed with water, dried over anhydrous magnesiumsulfate, filtered and evaporated under reduced pressure. The residue waspurified by column chromatography over silica, eluting withi-hexane/ethyl acetate (1:1) followed by i-hexane/ethyl acetate (1:4) togive the sub-title compound (0.43 g).

MS (ESI) 640 [M+H]⁺.

i)6-[[3,5-Dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]methyl]-5-[[(4S)-4-hydroxy-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

A solution of the product of part h) (0.43 g) and trifluoroacetic acid(0.5 ml) in DCM (10 ml) was stirred for 72 hours. It was concentrated invacuo, diluted with sodium bicarbonate solution, and extracted withethyl acetate, the organic extracts washed with water, dried overanhydrous magnesium sulfate, filtered and evaporated under reducedpressure. The residue was purified by column chromatography over silica,eluting with ethyl acetate then ethyl acetate/methanol (9:1) to give thetitle compound (30 mg).

MS (APCI) 526 [M+H]⁺.

δ¹H_(DMSO) 1.44-1.46 (6H, m), 2.16-2.19 (3H, m), 2.53-2.55 (3H, m),3.17-3.19 (3H, m), 3.48-4.14 (6H, m), 4.38 (1H, s, br), 4.60-4.80 (1H,m), 5.48-5.52 (1H, m), 7.46 (1H, dt), 8.87 (2H, t).

EXAMPLE 26-[[3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazol-4-yl]methyl]-5-[[(4S)-4-hydroxy-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

a)5-[[(4S)-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-2-isoxazolidinyl]carbonyl]-6-[[3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazol-4-yl]methyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

To a solution of the product of example 1 part g) (0.73 g) in chloroform(25 ml) was added pyridin-2-ylhydrazine (0.28 g) and the mixture stirredfor 48 hr. It was washed with water, dried over anhydrous magnesiumsulfate, filtered and evaporated under reduced pressure. The residue waspurified by column chromatography over silica, eluting with i-hexanefollowed by i-hexane/ethyl acetate (1:1) to give the sub-title compound(0.28 g).

MS (ESI) 639 [M+H]⁺.

b)6-[[3,5-Dimethyl-1-(2-pyridinyl)-1H-pyrazol-4-yl]methyl]-5-[[(4S)-4-hydroxy-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

A solution of the product of part a) (0.28 g) and trifluoroacetic acid(0.5 ml) in DCM (10 ml) was stirred for 72 hours. It was concentrated invacuo, diluted with sodium bicarbonate solution, and extracted withethyl acetate, the organic extracts washed with water, dried overanhydrous magnesium sulfate, filtered and evaporated under reducedpressure. The residue was purified by column chromatography over silica,eluting with ethyl acetate then ethyl acetate/methanol (49:1) to givethe title compound (88 mg).

MS (APCI) 525 [M+H]⁺.

δ ¹H_(DMSO) 1.44-1.47 (6H, m), 2.17-2.19 (3H, m), 2.56-2.58 (3H, m),3.47-4.14 (6H, m), 4.38 (1H, s, br), 4.60-4.80 (1H, m), 5.51-5.52 (1H,m), 7.30-7.34 (1H, m), 7.80 (1H, d), 7.95 (1H, dt), 8.45-8.47 (1H, m).

EXAMPLE 3(S)-2-[[6-[[3,5-Dimethyl-1-(2-thiazolyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-isoxazolidinol

A mixture of(S)-2-[[6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-isoxazolidinol(237 mg), 2-bromothiazole (237 mg), copper(I) iodide (20 mg),trans-cyclohexane-1,2-diamine (15 mg) and potassium carbonate (145 mg)were heated at 100° C. in 1,4-dioxane(1 ml) for 24 hours. The reactionmixture was concentrated to dryness and purified by chromatography onSiO₂ (Biotage cartridge) (eluting with EtOAc to 5% MeOH in EtOAc) andsubsequently reverse phase chromatography to give the title compound asa white solid (110 mg).

MS (APCI+ve) M+H=531.1.

δ ¹H_(DMSO,) 120° C. 1.47 (6H, d), 2.17 (3H, s), 2.60 (3H, s), 3.20 (3H,s), 3.46 (1H, d), 3.75 (1H, d), 3.89-3.95 (2H, m), 3.89 (2H, s), 4.46(1H, sep), 4.70 (1H, s), 5.08 (1H, s), 7.38 (1H, d), 7.56 (1H, d).

Pharmacological Data Inhibition of PMA/Ionomycin-Stimulated PeripheralBlood Mononuclear Cell Proliferation

The assay for PMA/ionomycin-stimulated PBMC proliferation was performedin 96-well flat-bottomed microtitre plates. Compounds were prepared as10 mM stock solutions in dimethyl sulfoxide. A 50-fold dilution of thiswas prepared in RPMI and serial dilutions were prepared from thissolution. 10 μl of the 50-fold diluted stock, or dilutions of it, wereadded to the well to give concentrations in the assay starting at 9.5 μMand going down. Into each well was placed 1×10⁵ PBMC, prepared fromhuman peripheral blood from a single donor, in RPMI1640 mediumsupplemented with 10% human serum, 2 mM glutamine andpenicillin/streptomycin. Phorbol myristate acetate (PMA) (0.5 ng/mlfinal concentration) and ionomycin (500 ng/ml final concentration) wereadded to these cells in supplemented RPMI1640 medium (as above) so thatthe final volume of the assay was 0.2 ml. The cells were incubated at37° C. in a humidified atmosphere at 5% carbon dioxide for 72 hours.³H-Thymidine (0.5 μCi) was added for the final 6 hours of theincubation. The level of radioactivity incorporated by the cells wasthen determined and this is a measure of proliferation.

The compounds of the Examples were found to exhibit an IA₅₀ value ofless than 1×10⁻⁶ M in the above test. Of the specific examples, examples1 had a PIA₅₀ of 8.3 and Example 3 had a PIA₅₀ of 9.07 in the abovetest.

1. A method of inhibiting the proliferation of T cells, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of formula (I):

wherein R¹ and R² each independently represent C₁₋₆alkyl, C₃₋₆alkenyl,C₃₋₅cycloalkylC₁₋₃alkyl or C₃₋₆cycloalkyl, each of which is optionallysubstituted by 1 to 3 halogen atoms; Q is CR⁴R⁵, in which R⁴ ishydrogen, fluorine or C₁₋₆ alkyl and R⁵ is hydrogen, fluorine orhydroxy; Ar is a 5- to 10-membered aromatic ring system in which up to 4ring atoms are optionally heteroatoms independently selected from thegroup consisting of nitrogen, oxygen and sulphur, the ring system beingoptionally substituted by one or more substituents independentlyselected from the group consisting of C₁₋₄alkyl (optionally substitutedby 1, 2 or 3 hydroxy or halo groups), C₁₋₄alkoxy, halogen,C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylthio, C₁₋₄alkoxycarbonyl, C₂₋₄alkanoyl,oxo, thioxo, nitro, cyano, —N(R⁶)R⁷, —(CH₂)_(p)N(R⁸)R⁹, hydroxy,C₁₋₄alkylsulphonyl, C₁₋₄alkylsulphinyl, carbamoyl, C₁₋₄alkylcarbamoyl,di-(C₁₋₄alkyl)carbamoyl, carboxy, SO₂N(R⁸)R⁹; Ar² is a 5 or 6 memberedaromatic ring containing up to 4 heteroatoms independently selected fromthe group consisting of nitrogen, sulphur or oxygen, and which isoptionally substituted by one or more groups independently selected fromthe group consisting of C₁₋₄alkyl (optionally substituted by 1, 2 or 3hydroxy or halo groups), C₁₋₄alkoxy, halogen, C₁₋₄alkoxyC₁₋₄alkyl,C₁₋₄alkylthio, C₁₋₄alkoxycarbonyl, C₂₋₄alkanoyl, oxo, thioxo, nitro,cyano, —N(R⁶)R⁷, —(CH₂)_(p)N(R⁸)R⁹, hydroxy, C₁₋₄alkylsulphonyl,C₁₋₄alkylsulphinyl, carbamoyl, C₁₋₄alkylcarbamoyl,di-(C₁₋₄alkyl)carbamoyl, carboxy, SO₂N(R⁸)R⁹; p is 1 to 4; R⁶ and R⁷each independently represent a hydrogen atom, C₁₋₄alkanoyl or C₁₋₄alkylgroup, or together with the nitrogen atom to which they are attachedform a 5- to 7-membered saturated heterocyclic ring optionallycontaining a further O, S, NH or N-alkyl group; R⁸ and R⁹ eachindependently represent a hydrogen atom, C₁₋₄alkanoyl or C₁₋₄alkylgroup, or together with the nitrogen atom to which they are attachedform a 5- to 7-membered saturated heterocyclic ring optionallycontaining a further O, S, NH or N-alkyl group; or a pharmaceuticallyacceptable salt thereof, provided that the compound is other than5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methyl-6-[5-methyl-3-phenyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dioneor6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dioneor a pharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein R¹ is C₁₋₆ alkyl.
 3. The method of claim 1, wherein R² ismethyl.
 4. The method of claim 1, wherein Q is CH₂.
 5. The method ofclaim 1, wherein Ar is a 5 or 6-membered aromatic ring system wherein upto 2 ring atoms are optionally heteroatoms independently selected fromthe group consisting of nitrogen, oxygen and sulphur, the ring systembeing optionally substituted by one or more substituents independentlyselected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, halogen,dihaloC₁₋₄alkyl, trihaloC₁₋₄alkyl, oxo, thioxo, cyano andC₁₋₄alkylsulphonyl.
 6. The method of claim 5, wherein Ar is a group ofsub-formula (I):

wherein R¹⁰ and R¹¹ are independently selected from H, C₁₋₄alkyl, orhaloC₁₋₄alkyl.
 7. The method of claim 1, wherein Ar² is other thanphenyl.
 8. The method of claim 7, wherein Ar² contains at least oneheteroatom.
 9. The method of claim 1, wherein Ar² is a 5 or 6-memberedaromatic ring system wherein up to 3 ring atoms are optionallyheteroatoms independently selected from the group consisting ofnitrogen, oxygen and sulphur, the ring system being optionallysubstituted by one or more substituents independently selected fromC₁₋₄alkyl, C₁₋₄alkoxy, halogen, dihaloC₁₋₄alkyl, trihaloC₁₋₄alkyl, oxo,thioxo, cyano and C₁₋₄alkylsulphonyl.
 10. The method of claim 9, whereinAr² is pyridinyl or pyrimidinyl.
 11. The method of claim 9, wherein Ar²is thiazolyl.
 12. The method of claim 1, wherein the compound isselected from the group consisting of(S)-2-[[6-[[3,5-Dimethyl-1-(2-thiazolyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-isoxazolidinoland pharmaceutically acceptable salts thereof.
 13. A method of effectingimmunosuppression, comprising administering to a patient in need thereofa therapeutically effective amount of a compound of formula (I):

wherein R¹ and R² each independently represent C₁₋₆alkyl, C₃₋₆alkenyl,C₃₋₅cycloalkylC₁₋₃alkyl or C₃₋₆cycloalkyl, each of which is optionallysubstituted by 1 to 3 halogen atoms; Q is CR⁴R⁵, in which R⁴ ishydrogen, fluorine or C₁₋₆ alkyl and R⁵ is hydrogen, fluorine orhydroxy; Ar is a 5- to 10-membered aromatic ring system in which up to 4ring atoms are optionally heteroatoms independently selected from thegroup consisting of nitrogen, oxygen and sulphur, the ring system beingoptionally substituted by one or more substituents independentlyselected from the group consisting of C₁₋₄alkyl (optionally substitutedby 1, 2 or 3 hydroxy or halo groups), C₁₋₄alkoxy, halogen,C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylthio, C₁₋₄alkoxycarbonyl, C₂₋₄alkanoyl,oxo, thioxo, nitro, cyano, —N(R⁶)R⁷, —(CH₂)_(p)N(R⁸)R⁹, hydroxy,C₁₋₄alkylsulphonyl, C₁₋₄alkylsulphinyl, carbamoyl, C₁₋₄alkylcarbamoyl,di-(C₁₋₄alkyl)carbamoyl, carboxy, SO₂N(R⁸)R⁹; Ar² is a 5 or 6 memberedaromatic ring containing up to 4 heteroatoms independently selected fromthe group consisting of nitrogen, sulphur or oxygen, and which isoptionally substituted by one or more groups independently selected fromthe group consisting of C₁₋₄alkyl (optionally substituted by 1, 2 or 3hydroxy or halo groups), C₁₋₄alkoxy, halogen, C₁₋₄alkoxyC₁₋₄alkyl,C₁₋₄alkylthio, C₁₋₄alkoxycarbonyl, C₂₋₄alkanoyl, oxo, thioxo, nitro,cyano, —N(R⁶)R⁷, —(CH₂)_(p)N(R⁸)R⁹, hydroxy, C₁₋₄alkylsulphonyl,C₁₋₄alkylsulphinyl, carbamoyl, C₁₋₄alkylcarbamoyl,di-(C₁₋₄alkyl)carbamoyl, carboxy, SO₂N(R⁸)R⁹; p is 1 to 4; R⁶ and R⁷each independently represent a hydrogen atom, C₁₋₄alkanoyl or C₁₋₄alkylgroup, or together with the nitrogen atom to which they are attachedform a 5- to 7-membered saturated heterocyclic ring optionallycontaining a further O, S, NH or N-alkyl group; R⁸ and R⁹ eachindependently represent a hydrogen atom, C₁₋₄alkanoyl or C₁₋₄alkylgroup, or together with the nitrogen atom to which they are attachedform a 5- to 7-membered saturated heterocyclic ring optionallycontaining a further O, S, NH or N-alkyl group; or a pharmaceuticallyacceptable salt thereof, provided that the compound is other than5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methyl-6-[5-methyl-3-phenyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dioneor6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dioneor a pharmaceutically acceptable salt thereof.
 14. The method of claim13, wherein R¹ is C₁₋₆ alkyl.
 15. The method of claim 13, wherein R² ismethyl.
 16. The method of claim 13, wherein Q is CH₂.
 17. The method ofclaim 13, wherein Ar is a 5 or 6-membered aromatic ring system whereinup to 2 ring atoms are optionally heteroatoms independently selectedfrom the group consisting of nitrogen, oxygen and sulphur, the ringsystem being optionally substituted by one or more substituentsindependently selected from the group consisting of C₁₋₄alkyl,C₁₋₄alkoxy, halogen, dihaloC₁₋₄alkyl, trihaloC₁₋₄alkyl, oxo, thioxo,cyano and C₁₋₄alkylsulphonyl.
 18. The method of claim 17, wherein Ar isa group of sub-formula (I):

wherein R¹⁰ and R¹¹ are independently selected from H, C₁₋₄alkyl, orhaloC₁₋₄alkyl.
 19. The method of claim 13, wherein Ar² is other thanphenyl.
 20. The method of claim 19, wherein Ar² contains at least oneheteroatom.
 21. The method of claim 13, wherein Ar² is a 5 or 6-memberedaromatic ring system wherein up to 3 ring atoms are optionallyheteroatoms independently selected from the group consisting ofnitrogen, oxygen and sulphur, the ring system being optionallysubstituted by one or more substituents independently selected fromC₁₋₄alkyl, C₁₋₄alkoxy, halogen, dihaloC₁₋₄alkyl, trihaloC₁₋₄alkyl, oxo,thioxo, cyano and C₁₋₄alkylsulphonyl.
 22. The method of claim 21,wherein Ar² is pyridinyl or pyrimidinyl.
 23. The method of claim 21,wherein Ar² is thiazolyl.
 24. The method of claim 13, wherein thecompound is selected from the group consisting of(S)-2-[[6-[[3,5-Dimethyl-1-(2-thiazolyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-isoxazolidinoland pharmaceutically acceptable salts thereof.
 25. A method of treatinga reversible obstructive airways disease in a patient suffering from thedisease, comprising administering to the patient a therapeuticallyeffective amount of a compound of formula (I):

wherein R¹ and R² each independently represent C₁₋₆alkyl, C₃₋₆alkenyl,C₃₋₅cycloalkylC₁₋₃alkyl or C₃₋₆cycloalkyl, each of which is optionallysubstituted by 1 to 3 halogen atoms; Q is CR⁴R⁵, in which R⁴ ishydrogen, fluorine or C₁₋₆ alkyl and R⁵ is hydrogen, fluorine orhydroxy; Ar is a 5- to 10-membered aromatic ring system in which up to 4ring atoms are optionally heteroatoms independently selected from thegroup consisting of nitrogen, oxygen and sulphur, the ring system beingoptionally substituted by one or more substituents independentlyselected from the group consisting of C₁₋₄alkyl (optionally substitutedby 1, 2 or 3 hydroxy or halo groups), C₁₋₄alkoxy, halogen,C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylthio, C₁₋₄alkoxycarbonyl, C₂₋₄alkanoyl,oxo, thioxo, nitro, cyano, —N(R⁶)R⁷, —(CH₂)_(p)N(R⁸)R⁹, hydroxy,C₁₋₄alkylsulphonyl, C₁₋₄alkylsulphinyl, carbamoyl, C₁₋₄alkylcarbamoyl,di-(C₁₋₄alkyl)carbamoyl, carboxy, SO₂N(R⁸)R⁹; Ar² is a 5 or 6 memberedaromatic ring containing up to 4 heteroatoms independently selected fromthe group consisting of nitrogen, sulphur or oxygen, and which isoptionally substituted by one or more groups independently selected fromthe group consisting of C₁₋₄alkyl (optionally substituted by 1, 2 or 3hydroxy or halo groups), C₁₋₄alkoxy, halogen, C₁₋₄alkoxyC₁₋₄alkyl,C₁₋₄alkylthio, C₁₋₄alkoxycarbonyl, C₂₋₄alkanoyl, oxo, thioxo, nitro,cyano, —N(R⁶)R⁷, —(CH₂)_(p)N(R⁸)R⁹, hydroxy, C₁₋₄alkylsulphonyl,C₁₋₄alkylsulphinyl, carbamoyl, C₁₋₄alkylcarbamoyl,di-(C₁₋₄alkyl)carbamoyl, carboxy, SO₂N(R⁸)R⁹; p is 1 to 4; R⁶ and R⁷each independently represent a hydrogen atom, C₁₋₄alkanoyl or C₁₋₄alkylgroup, or together with the nitrogen atom to which they are attachedform a 5- to 7-membered saturated heterocyclic ring optionallycontaining a further O, S, NH or N-alkyl group; R⁸ and R⁹ eachindependently represent a hydrogen atom, C₁₋₄alkanoyl or C₁₋₄alkylgroup, or together with the nitrogen atom to which they are attachedform a 5- to 7-membered saturated heterocyclic ring optionallycontaining a further O, S, NH or N-alkyl group; or a pharmaceuticallyacceptable salt thereof, provided that the compound is other than5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methyl-6-[5-methyl-3-phenyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dioneor6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dioneor a pharmaceutically acceptable salt thereof.
 26. The method of claim25, wherein the obstructive airways disease is chronic obstructivepulmonary disease.
 27. The method of claim 25, wherein R¹ is C₁₋₆ alkyl.28. The method of claim 25, wherein R² is methyl.
 29. The method ofclaim 25, wherein Q is CH₂.
 30. The method of claim 25, wherein Ar is a5 or 6-membered aromatic ring system wherein up to 2 ring atoms areoptionally heteroatoms independently selected from the group consistingof nitrogen, oxygen and sulphur, the ring system being optionallysubstituted by one or more substituents independently selected from thegroup consisting of C₁₋₄alkyl, C₁₋₄alkoxy, halogen, dihaloC₁₋₄alkyl,trihaloC₁₋₄alkyl, oxo, thioxo, cyano and C₁₋₄alkylsulphonyl.
 31. Themethod of claim 30, wherein Ar is a group of sub-formula (I):

wherein R¹⁰ and R¹¹ are independently selected from H, C₁₋₄alkyl, orhaloC₁₋₄alkyl.
 32. The method of claim 25, wherein Ar² is other thanphenyl.
 33. The method of claim 32, wherein Ar² contains at least oneheteroatom.
 34. The method of claim 25, wherein Ar² is a 5 or 6-memberedaromatic ring system wherein up to 3 ring atoms are optionallyheteroatoms independently selected from the group consisting ofnitrogen, oxygen and sulphur, the ring system being optionallysubstituted by one or more substituents independently selected fromC₁₋₄alkyl, C₁₋₄alkoxy, halogen, dihaloC₁₋₄alkyl, trihaloC₁₋₄alkyl, oxo,thioxo, cyano and C₁₋₄alkylsulphonyl.
 35. The method of claim 34,wherein Ar² is pyridinyl or pyrimidinyl.
 36. The method of claim 34,wherein Ar² is thiazolyl.
 37. The method of claim 25, wherein thecompound is selected from the group consisting of(S)-2-[[6-[[3,5-Dimethyl-1-(2-thiazolyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-isoxazolidinoland pharmaceutically acceptable salts thereof.
 38. A method of treatingcancer in a patient suffering from the cancer, comprising administeringto the patient a therapeutically effective amount of a compound offormula (I):

wherein R¹ and R² each independently represent C₁₋₆alkyl, C₃₋₆alkenyl,C₃₋₅cycloalkylC₁₋₃alkyl or C₃₋₆cycloalkyl, each of which is optionallysubstituted by 1 to 3 halogen atoms; Q is CR⁴R⁵, in which R⁴ ishydrogen, fluorine or C₁₋₆ alkyl and R⁵ is hydrogen, fluorine orhydroxy; Ar is a 5- to 10-membered aromatic ring system in which up to 4ring atoms are optionally heteroatoms independently selected from thegroup consisting of nitrogen, oxygen and sulphur, the ring system beingoptionally substituted by one or more substituents independentlyselected from the group consisting of C₁₋₄alkyl (optionally substitutedby 1, 2 or 3 hydroxy or halo groups), C₁₋₄alkoxy, halogen,C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylthio, C₁₋₄alkoxycarbonyl, C₂₋₄alkanoyl,oxo, thioxo, nitro, cyano, —N(R⁶)R⁷, —(CH₂)_(p)N(R⁸)R⁹, hydroxy,C₁₋₄alkylsulphonyl, C₁₋₄alkylsulphinyl, carbamoyl, C₁₋₄alkylcarbamoyl,di-(C₁₋₄alkyl)carbamoyl, carboxy, SO₂N(R⁸)R⁹; Ar² is a 5 or 6 memberedaromatic ring containing up to 4 heteroatoms independently selected fromthe group consisting of nitrogen, sulphur or oxygen, and which isoptionally substituted by one or more groups independently selected fromthe group consisting of C₁₋₄alkyl (optionally substituted by 1, 2 or 3hydroxy or halo groups), C₁₋₄alkoxy, halogen, C₁₋₄alkoxyC₁₋₄alkyl,C₁₋₄alkylthio, C₁₋₄alkoxycarbonyl, C₂₋₄alkanoyl, oxo, thioxo, nitro,cyano, —N(R⁶)R⁷, —(CH₂)_(p)N(R⁸)R⁹, hydroxy, C₁₋₄alkylsulphonyl,C₁₋₄alkylsulphinyl, carbamoyl, C₁₋₄alkylcarbamoyl,di-(C₁₋₄alkyl)carbamoyl, carboxy, SO₂N(R⁸)R⁹; p is 1 to 4; R⁶ and R⁷each independently represent a hydrogen atom, C₁₋₄alkanoyl or C₁₋₄alkylgroup, or together with the nitrogen atom to which they are attachedform a 5- to 7-membered saturated heterocyclic ring optionallycontaining a further O, S, NH or N-alkyl group; R⁸ and R⁹ eachindependently represent a hydrogen atom, C₁₋₄alkanoyl or C₁₋₄alkylgroup, or together with the nitrogen atom to which they are attachedform a 5- to 7-membered saturated heterocyclic ring optionallycontaining a further O, S, NH or N-alkyl group; or a pharmaceuticallyacceptable salt thereof, provided that the compound is other than5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methyl-6-[5-methyl-3-phenyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dioneor6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dioneor a pharmaceutically acceptable salt thereof.
 39. The method of claim38, wherein R¹ is C₁₋₆ alkyl.
 40. The method of claim 38, wherein R² ismethyl.
 41. The method of claim 38, wherein Q is CH₂.
 42. The method ofclaim 38, wherein Ar is a 5 or 6-membered aromatic ring system whereinup to 2 ring atoms are optionally heteroatoms independently selectedfrom the group consisting of nitrogen, oxygen and sulphur, the ringsystem being optionally substituted by one or more substituentsindependently selected from the group consisting of C₁₋₄alkyl,C₁₋₄alkoxy, halogen, dihaloC₁₋₄alkyl, trihaloC₁₋₄alkyl, oxo, thioxo,cyano and C₁₋₄alkylsulphonyl.
 43. The method of claim 42, wherein Ar isa group of sub-formula (I):

wherein R¹⁰ and R¹¹ are independently selected from H, C₁₋₄alkyl, orhaloC₁₋₄alkyl.
 44. The method of claim 38, wherein Ar² is other thanphenyl.
 45. The method of claim 44, wherein Ar² contains at least oneheteroatom.
 46. The method of claim 38, wherein Ar² is a 5 or 6-memberedaromatic ring system wherein up to 3 ring atoms are optionallyheteroatoms independently selected from the group consisting ofnitrogen, oxygen and sulphur, the ring system being optionallysubstituted by one or more substituents independently selected fromC₁₋₄alkyl, C₁₋₄alkoxy, halogen, dihaloC₁₋₄alkyl, trihaloC₁₋₄alkyl, oxo,thioxo, cyano and C₁₋₄alkylsulphonyl.
 47. The method of claim 46,wherein Ar² is pyridinyl or pyrimidinyl.
 48. The method of claim 46,wherein Ar² is thiazolyl.
 49. The method of claim 38, wherein thecompound is selected from the group consisting of(S)-2-[[6-[[3,5-Dimethyl-1-(2-thiazolyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-isoxazolidinoland pharmaceutically acceptable salts thereof.